PreScription DigitaL ThErapEutic for Patients with Insomnia (SLEEP-I): a protocol for a pragmatic randomised controlled trial.

INTRODUCTION: Cognitive behavioural therapy for insomnia (CBT-I) is effective at treating chronic insomnia, yet in-person CBT-I can often be challenging to access. Prior studies have used technology to bridge barriers but have been unable to extensively assess the impact of the digital therapeutic on real-world patient experience and multidimensional outcomes. Among patients with insomnia, our aim is to determine the impact of a prescription digital therapeutic (PDT) (PEAR-003b, FDA-authorised as Somryst; herein called PDT) that provides mobile-delivered CBT-I on patient-reported outcomes (PROs) and healthcare utilisation. METHODS AND ANALYSIS: We are conducting a pragmatically designed, prospective, multicentre randomised controlled trial that leverages Hugo, a unique patient-centred health data-aggregating platform for data collection and patient follow-up from Hugo Health. A total of 100 participants with insomnia from two health centres will be enrolled onto the Hugo Health platform, provided with a linked Fitbit (Inspire 2) to track activity and then randomised 1:1 to receive (or not) the PDT for mobile-delivered CBT-I (Somryst). The primary outcome is a change in the insomnia severity index score from baseline to 9-week postrandomisation. Secondary outcomes include healthcare utilisation, health utility scores and clinical outcomes; change in sleep outcomes as measured with sleep diaries and a change in individual PROs including depressive symptoms, daytime sleepiness, health status, stress and anxiety. For those allocated to the PDT, we will also assess engagement with the PDT. ETHICS AND DISSEMINATION: The Institutional Review Boards at Yale University and the Mayo Clinic have approved the trial protocol. This trial will provide important data to patients, clinicians and policymakers about the impact of the PDT device delivering CBT-I on PROs, clinical outcomes and healthcare utilisation. Findings will be disseminated to participants, presented at professional meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04909229.

Patient Engagement With a Game-Based Digital Therapeutic for the Treatment of Opioid Use Disorder: Protocol for a Randomized Controlled Open-Label, Decentralized Trial.

BACKGROUND: Prescription digital therapeutics are software-based disease treatments that are regulated by the US Food and Drug Administration; the reSET-O prescription digital therapeutic was authorized in 2018 and delivers behavioral treatment for individuals receiving buprenorphine for opioid use disorder. Although reSET-O improves outcomes for individuals with opioid use disorder, most of the therapeutic content is delivered as narrative text. PEAR-008 is an investigational device based on reSET-O that uses an interactive, game-based platform to deliver similar therapeutic content designed to enhance patient engagement, which may further improve treatment outcomes. OBJECTIVE: We aim to investigate how participants interact with the prescription digital therapeutic's new content delivery format. Secondary objectives include evaluating treatment success, symptoms of co-occurring mental health disorders, recovery capital, and skill development. METHODS: Due to the COVID-19 pandemic, this study was redesigned using a decentralized model because it was not possible to conduct medication initiation and study visits in person, as initially intended. A decentralized, randomized controlled trial design will be utilized to compare patient engagement with PEAR-008 and that with reSET-O using both subjective and objective assessments. The study population will consist of approximately 130 individuals with opioid use disorder (based on Diagnostic and Statistical Manual of Mental Disorders 5 criteria) who have recently started buprenorphine treatment for opioid use disorder. Participants will be virtually recruited and randomly assigned to receive either PEAR-008 or reSET-O. All study sessions will be virtual, and the duration of the study is 12 weeks. The primary outcome measure of engagement is operationalized as the number of active sessions per week with either PEAR-008 or reSET-O. (An active session is any session that contains some active participation in the app, such as navigating to a different screen, engaging with a learning module, or responding to a notification.) Subjective dimensions of engagement will be assessed with participant surveys. The hypothesis is that PEAR-008 will have significantly greater participant engagement than reSET-O. RESULTS: As of February 2021, participant enrollment is ongoing. CONCLUSIONS: This randomized controlled trial will investigate if changing the delivery format and enhancing the content of a prescription digital therapeutic for opioid use disorder will affect how participants use and interact with the prescription digital therapeutic. The study design may serve as a useful model for conducting decentralized studies in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov NCT04542642; https://clinicaltrials.gov/ct2/show/NCT04542642. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/32759.

Randomized clinical trials towards a single-visit cure for chronic hepatitis C: Oral GSK2878175 and injectable RG-101 in chronic hepatitis C patients and long-acting injectable GSK2878175 in healthy participants.

Single-visit cures for chronic hepatitis C are lacking. We conducted two clinical studies towards the goal of developing a regimen for single-visit cure. In a randomized, open-label, Phase 2 study (RG101-04), investigators enrolled 26 adult chronic hepatitis C patients to evaluate safety and efficacy of single subcutaneous injection of RG-101 (4 mg/kg) and daily oral tablets of GSK2878175 (20 mg) for 6, 9 or 12 weeks. In another randomized, double-blind, single dose Phase 1 study (RG101-06), investigators enrolled 18 healthy men to assess safety and PK of GSK2878175 long-acting injectable at 100, 200 or 400 mg. In RG101-04, SVR48 rates were 50%, 56% and 89%, for the 6, 9 and 12 weeks treatment arms, respectively. All AEs were mild or moderate in severity (≤Grade 2). In RG101-06 at 400 mg, the mean duration of GSK2878175 plasma levels above in vitro therapeutic concentrations for GT1b was 41 days. All AEs were Grade 2 or less. In conclusion, single injection of RG-101 combined with 12 weeks of GSK2878175 oral tablets was generally well tolerated and resulted in high SVR rates in chronic hepatitis C patients. Single injections of GSK2878175 long-acting injectable were also well tolerated; however, higher doses would be required if used in combination with RG-101 to achieve the SVR rates observed in the oral combination study to enable a single-visit curative regimen.

Applications of Bayesian statistical methodology to clinical trial design: A case study of a phase 2 trial with an interim futility assessment in patients with knee osteoarthritis.

Development of new pharmacological treatments for osteoarthritis that address unmet medical needs in a competitive market place is challenging. Bayesian approaches to trial design offer advantages in defining treatment benefits by addressing clinically relevant magnitude of effects relative to comparators and in optimizing efficiency in analysis. Such advantages are illustrated by a motivating case study, a proof of concept, and dose finding study in patients with osteoarthritis. Patients with osteoarthritis were randomized to receive placebo, celecoxib, or 1 of 4 doses of galcanezumab. Primary outcome measure was change from baseline WOMAC pain after 8 weeks of treatment. Literature review of clinical trials with targeted comparator therapies quantified treatment effects versus placebo. Two success criteria were defined: one to address superiority to placebo with adequate precision and another to ensure a clinically relevant treatment effect. Trial simulations used a Bayesian dose response and longitudinal model. An interim analysis for futility was incorporated. Simulations indicated the study had ≥85% power to detect a 14-mm improvement and ≤1% risk for a placebo-like drug to pass. The addition of the second success criterion substantially reduced the risk of an inadequate, weakly efficacious drug proceeding to future development. The study was terminated at the interim analysis due to inadequate analgesic efficacy. A Bayesian approach using probabilistic statements enables clear understanding of success criteria, leading to informed decisions for study conduct. Incorporating an interim analysis can effectively reduce sample size, save resources, and minimize exposure of patients to an inadequate treatment.

Coding variants in PNPLA3 and TM6SF2 are risk factors for hepatic steatosis and elevated serum alanine aminotransferases caused by a glucagon receptor antagonist.

LY2409021 is a glucagon receptor antagonist that was associated with hepatic steatosis and elevated aminotransferases in phase 2 diabetes studies. We investigated the relationship between selected genetic variants and hepatic steatosis and elevated alanine aminotransferases (ALTs) associated with LY2409021. Patients participated in a 6-week placebo-controlled trial (I1R-MC-GLDI [GLDI], n = 246) and a 52-week placebo- and active comparator-controlled trial (I1R-MC-GLDJ [GLDJ], n = 158). GLDJ had endpoints at 6 months, including measures of hepatic fat fraction (HFF) by magnetic resonance imaging. The five genes tested were patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 and rs738491), transmembrane 6 superfamily member 2 (TM6SF2) (rs58542926), peroxisome proliferative activated receptor gamma coactivator 1 alpha (PPARGC1A) (rs4361373, rs3774921, rs2970849), adenylate cyclase 3 (ADCY3) (rs713586), and insulin-like growth factor 1 (IGF-1) (rs1520220). In GLDI, PNPLA3 I148M (P = 0.001) and TM6SF2 E167K (P = 0.001) were significantly associated with an increase in ALT at 6 weeks for LY2409021 but not for placebo. In GLDJ, PNPLA3 I148M showed the same effect (P = 0.007) on ALT at 6 months but the placebo or sitagliptin did not. In GLDJ, both PNPLA3 and TM6SF2 risk-allele carriers showed increases in HFF that were numerically greater but not statistically significant. The carriers of PNPLA3 and/or TM6SF2 risk alleles showed significantly increased ALT (GLDI, +13.28 U/L in carriers versus +4.84 U/L in noncarriers, P = 4 × 10-5; GLDJ, +14.6 U/L in carriers versus +1.7 in noncarriers, P = 0.0018) and HFF (GLDJ, +5.35% in carriers versus 2.38% in noncarriers, P = 0.048). Elevation of transaminase and HFF were also noted in the noncarriers but at a significantly lower degree. Conclusion: The carriers of PNPLA3 and/or TM6SF2 variant alleles are at risk for hepatic steatosis and elevated ALT levels caused by LY2409021, a glucagon receptor antagonist. More studies are needed to investigate if our observations are generalizable to hepatic steatosis caused by other medications. (Hepatology Communications 2018;2:561-570).

Evaluation of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy After Single and Multiple Dosings of LY3016859 in Healthy Subjects and Patients With Diabetic Nephropathy.

Two phase 1 studies (TGAA and TGAB) evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of LY3016859 (LY), a monoclonal antibody that binds epiregulin and transforming growth factor α (TGF-α), administered intravenously or subcutaneously. In TGAA, 56 healthy subjects received a single dose of LY (0.1-750 mg intravenously, 50 mg subcutaneously) or placebo. In TGAB part A, 15 patients with diabetic nephropathy (DN) received 2 doses of LY (10-750 mg intravenously) or placebo, and in TGAB part B, 45 patients with DN received 5 doses of LY (50-750 mg intravenously) or placebo. Pharmacokinetics, pharmacodynamics, anti-LY antibodies, and change in proteinuria and albuminuria were evaluated. Single and multiple doses of LY administered 3 weeks apart were well tolerated. Pharmacokinetics were nonlinear in healthy subjects and patients with DN, indicating target-mediated drug disposition. Epiregulin level increased in both studies, and TGF-α levels increased in the TGAB study, consistent with target engagement; however, LY treatment did not significantly reduce proteinuria or albuminuria in patients with DN. There was no obvious effect of LY on the disease-related biomarkers monocyte chemoattractant protein-1, synaptopodin, or transferrin. Although LY administration resulted in a high frequency of anti-LY antibodies, pharmacokinetics, target engagement, and efficacy were not impacted.

Factors associated with stroke, myocardial infarction, ischemic heart disease, unstable angina, or mortality in patients from real world clinical practice with newly-diagnosed type 2 diabetes and early glycemic control.

OBJECTIVES: The objective of this study was to identify factors associated with stroke, myocardial infarction (MI), all-cause mortality, or a diagnosis of ischemic heart disease (IHD) or unstable angina (UA), among patients newly-diagnosed with type 2 diabetes (T2DM) with no recent history of cardiovascular (CV) events who rapidly achieve and maintain HbA1c ≤8.0%. METHODS: Data were obtained from the Clinical Practice Research Datalink (CPRD) from January 1990 to December 2012. A nested case-control design was used with Cox proportional hazards analysis. Cases were identified by the first occurrence of stroke, MI, IHD, UA, or death within 5 years after HbA1c ≤ 8.0% was first reached (index date) following T2DM diagnosis. Controls were selected using a risk-set sampling approach and were matched 4:1 to cases using index date, exposure time, age, gender, and HbA1c at index date. RESULTS: A total of 11,426 T2DM patients met the inclusion criteria for cases. Of these, 5,261 experienced a CV event. Stroke was the most frequent CV event (40%), followed by IHD (29%), MI (22%), and UA (9%). Mean HbA1c ≥7.0% over the length of exposure (vs 6.5 to <7.0%) was associated with an increased risk of stroke, MI, and IHD. The use of anti-platelet medications at baseline was also associated with increased risk of stroke (HR = 1.82 [CI = 1.60-2.06]), MI (HR = 1.67 [CI = 1.38-2.03]), and IHD (HR = 1.85 [CI = 1.57-2.17]). Mean HbA1c < 6.0% was associated with increased risk of stroke (HR = 1.29 [CI = 1.02-1.63]) and IHD (HR = 1.65 [CI = 1.25-2.19]). Use of nitrate medications at baseline was associated with increased risk of MI (HR = 2.83 [CI = 2.24-3.57]), IHD (HR = 4.32 [CI = 3.57-5.22]), and UA (HR = 10.38 [CI = 7.67-14.03]). CONCLUSIONS: Early and sustained HbA1c control between 6.5 and <7.0% appears to be an important modifiable factor that helps reduce CV risk in patients with newly-diagnosed T2DM in real-world clinical practice.

Clinical Outcomes of Patients with Diabetes Who Exhibit Upper-Quartile Insulin Antibody Responses After Treatment with LY2963016 or Lantus® Insulin Glargine.

INTRODUCTION: We compared insulin antibody response (IAR) profiles in patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) who received LY2963016 insulin glargine (LY IGlar) or Lantus® insulin glargine (IGlar) and evaluated the potential relationship between higher IARs and clinical and safety outcomes with a focus on patients who exhibited antibody responses in the upper quartile. METHODS: Data from ELEMENT-1 (52-week open-label in T1D) and ELEMENT-2 (24-week, double-blind study in T2D) were analyzed. Maximum postbaseline IAR levels and proportions of patients in the upper quartile of maximum antibody percent binding (UQMAPB; patients with maximum postbaseline percent binding in the highest 25% of maximum values observed) were compared for differential treatment effects on clinical efficacy outcomes and incidence of adverse events. Continuous outcomes were analyzed by analysis of covariance. Categorical data were analyzed by the Cochran-Mantel-Haenszel or Breslow-Day test. RESULTS: In both studies (N = 532 evaluable patients with T1D; N = 730 with T2D), no statistically significant differences between LY IGlar and IGlar were observed for maximum antibody percent binding (MAPB) levels or for proportions of patients in the respective UQMAPB. No statistically significant differential treatment effects were observed in the relationship between MAPB and clinical efficacy and safety outcomes. CONCLUSIONS: Maximum postbaseline IAR levels and the proportion of patients with high IAR levels were similar for LY IGlar and IGlar. High antibody levels did not affect clinical outcomes. These results add further evidence supporting similar IARs of LY IGlar and IGlar. FUNDING: Eli Lilly and Company and Boehringer-Ingelheim.

The Discovery, Preclinical, and Early Clinical Development of Potent and Selective GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus (LY2881835, LY2922083, and LY2922470).

The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet ß-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.

Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of ß-Cell Function: Results From the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series.

OBJECTIVE: Standardized, reproducible, and feasible quantification of ß-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states. RESEARCH DESIGN AND METHODS: Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT). RESULTS: From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (∼50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from ∼0.3 to ∼0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations. CONCLUSIONS: Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use.

Evacetrapib alone or in combination with statins lowers lipoprotein(a) and total and small LDL particle concentrations in mildly hypercholesterolemic patients.

BACKGROUND: Potent CETP inhibitors reduce plasma concentrations of atherogenic lipoprotein biomarkers of cardiovascular risk. OBJECTIVES: To evaluate the effects of the cholesteryl ester transfer protein (CETP) inhibitor evacetrapib, as monotherapy or with statins, on atherogenic apolipoprotein B (apoB)-containing lipoproteins in mildly hypercholesterolemic patients. METHODS: VLDL and LDL particle concentrations and sizes (using nuclear magnetic resonance spectroscopy) and lipoprotein(a) concentration (using nephelometry) were measured at baseline and week 12 in a placebo-controlled trial of 393 patients treated with evacetrapib as monotherapy (30 mg/d, 100 mg/d, or 500 mg/d) or in combination with statins (100 mg plus simvastatin 40 mg/d, atorvastatin 20 mg/d, or rosuvastatin 10 mg/d; Clinicaltrials.gov Identifier: NCT01105975). RESULTS: Evacetrapib monotherapy resulted in significant placebo-adjusted dose-dependent decreases from baseline in Lp(a) (up to -40% with evacetrapib 500 mg), total LDL particle (LDL-P) (up to -54%), and small LDL particle (sLDL) (up to -95%) concentrations. Compared to statin alone, coadministration of evacetrapib and statins also resulted in significant reduction from baseline in Lp(a) (-31%), LDL-P (-22%), and sLDL (-60%) concentrations. The percentage of patients with concentrations above optimal concentrations for LDL-P (>1000 nmol/L) and sLDL (>600 nmol/L) decreased from 88% and 55% at baseline, respectively, to 20% and 12% at week 12, for patients treated with evacetrapib plus statins. Evacetrapib, alone or with statins, significantly increased LDL-P size. CONCLUSIONS: Evacetrapib, as monotherapy or with statins, significantly reduces the concentrations of atherogenic apoB-containing lipoproteins, including Lp(a), LDL-P, and sLDL.

Prognostic and predictive biomarkers of abdominal aortic aneurysm growth rate.

OBJECTIVES: To test the utility of clinical and circulating biomarkers to predict abdominal aortic aneurysm (AAA) growth rate and response to doxycycline therapy. METHODS: Plasma samples were obtained in the Pharmaceutical Aneurysm Stabilization Trial that tested the effect of doxycycline (n = 44) vs. placebo (n = 49) in patients with a 35-50 mm AAA. Approximately 200 biomarkers were evaluated in a candidate approach that included markers of matrix turnover and cathepsin S activity and a broad-based approach of predominantly inflammation-related and clinical biomarkers. RESULTS: In a recursive partitioning based analysis, total cholesterol, baseline AAA size, and apolipoprotein B were prognostic of AAA growth in the placebo group whereas elastin and biglycan degradation products were predictive of AAA growth with doxycycline treatment. Univariate analysis of these biomarkers showed that baseline total cholesterol (r = 0.38, unadjusted P = 0.011), apolipoprotein B (r = 0.41, unadjusted P = 0.005), and baseline AAA size (r = 0.35, unadjusted P = 0.013) correlated with AAA growth in the placebo but not the doxycycline group. Elastin fragments were associated with 18 month AAA growth (r = 0.33, unadjusted P = 0.031) in the doxycycline group. LIMITATIONS: Limitations of this study include small sample size, a retrospective growth analysis, and translatability of the method used to measure the analytes. CONCLUSIONS: This study implies that total cholesterol, baseline AAA size, and apolipoprotein B are predictors of AAA growth. Levels of elastin and biglycan fragments are predictive of doxycycline effects on AAA growth and provide a clue towards this unexpected negative effect.

Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies.

OBJECTIVE: Type 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The efficacy (HbA1c and glucose) and safety (serum aminotransferase) of once-daily oral administration of LY2409021 was assessed in two double-blind studies. Phase 2a study patients were randomized to 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks. Phase 2b study patients were randomized to 2.5, 10, or 20 mg LY2409021 or placebo for 24 weeks. RESULTS: LY2409021 produced reductions in HbA1c that were significantly different from placebo over both 12 and 24 weeks. After 12 weeks, least squares (LS) mean change from baseline in HbA1c was -0.83% (10 mg), -0.65% (30 mg), and -0.66% (60 mg) (all P < 0.05) vs. placebo, 0.11%. After 24 weeks, LS mean change from baseline in HbA1c was -0.45% (2.5 mg), -0.78% (10 mg, P < 0.05), -0.92% (20 mg, P < 0.05), and -0.15% with placebo. Increases in serum aminotransferase, fasting glucagon, and total fasting glucagon-like peptide-1 (GLP-1) were observed; levels returned to baseline after drug washout. Fasting glucose was also lowered with LY2409021 at doses associated with only modest increases in aminotransferases (mean increase in alanine aminotransferase [ALT] ≤10 units/L). The incidence of hypoglycemia in the LY2409021 groups was not statistically different from placebo. CONCLUSIONS: In patients with type 2 diabetes, glucagon receptor antagonist treatment significantly lowered HbA1c and glucose levels with good overall tolerability and a low risk for hypoglycemia. Modest, reversible increases in serum aminotransferases were observed.

Pharmacokinetics and pharmacodynamics of the cathepsin S inhibitor, LY3000328, in healthy subjects.

AIM: The aim of this study was to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of LY3000328 when administered as single escalating doses to healthy volunteers. METHODS: This was a phase 1, placebo-controlled, dose escalation study with LY3000328 in 21 healthy male volunteers. Subjects were administered escalating LY3000328 doses up to 300 mg with food in this single dose study. Blood samples were collected at set times post-dose for the assessment of LY3000328 pharmacokinetics and the measurement of cathepsin S (CatS) activity, CatS mass and calculated CatS specific activity. RESULTS: All doses of LY3000328 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of LY3000328 was measured ex vivo showing a biphasic response to LY3000328, where CatS activity declines, then returns to baseline, and then increases to a level above baseline. CatS mass was also assessed post-dose which increased in a dose-dependent manner, and continued to increase after LY3000328 had been cleared from the body. CatS specific activity was additionally calculated to normalize CatS activity for changes in CatS mass. This demonstrated the increase in CatS activity was attributable to the increase in CatS mass detected in plasma. CONCLUSION: A specific inhibitor of CatS which is cleared quickly from plasma may produce a transient decrease in plasma CatS activity which is followed by a more prolonged increase in plasma CatS mass which may have implications for the future clinical development of inhibitors of CatS.

Physician preferences for extra-glycemic effects of type 2 diabetes treatments.

INTRODUCTION: The purpose of this study was to quantify United States (US) and United Kingdom (UK) physicians' preferences for attributes of type 2 diabetes treatments. METHODS: Samples of general practitioners (GPs) and endocrinologists in the US (n = 204) and the UK (n = 200) completed a discrete-choice experiment in which respondents chose between pairs of hypothetical type 2 diabetes treatments in a series of trade-off questions. The questions described hypothetical injectable treatments with differing levels of attributes, such as glucose control and treatment side effects. Relative importance of attributes was estimated by a multivariate regression model for limited dependent variables. These results were used to calculate how the predicted probability of choosing hypothetical type 2 diabetes treatments varies with changes in given attributes. RESULTS: The most important attributes to physicians were glucose control, risk of a fatal myocardial infarction (MI), and weight change. For US physicians, glucose control was about twice as important as gastrointestinal side effects, 5 times more important than changes in depression symptoms, and 20 times more important than liver monitoring. For UK physicians, reduction in MI risk was about 1.5 times more important than glucose control, 2.5 times more important than gastrointestinal side effects, and 10 times more important than liver-monitoring requirements. Preferences were similar among physicians in the US and the UK and among GPs and endocrinologists. CONCLUSIONS: Physicians valued type 2 diabetes treatments that go beyond glycemic control, although mitigating different complications and comorbidities was not equally as important.

The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes.

Fibroblast growth factor 21 (FGF21) is a recently discovered metabolic regulator. Exogenous FGF21 produces beneficial metabolic effects in animal models; however, the translation of these observations to humans has not been tested. Here, we studied the effects of LY2405319 (LY), a variant of FGF21, in a randomized, placebo-controlled, double-blind proof-of-concept trial in patients with obesity and type 2 diabetes. Patients received placebo or 3, 10, or 20 mg of LY daily for 28 days. LY treatment produced significant improvements in dyslipidemia, including decreases in low-density lipoprotein cholesterol and triglycerides and increases in high-density lipoprotein cholesterol and a shift to a potentially less atherogenic apolipoprotein concentration profile. Favorable effects on body weight, fasting insulin, and adiponectin were also detected. However, only a trend toward glucose lowering was observed. These results indicate that FGF21 is bioactive in humans and suggest that FGF21-based therapies may be effective for the treatment of selected metabolic disorders.

Homocysteine levels and dementia risk in Yoruba and African Americans.

BACKGROUND: High levels of homocysteine have been associated with increased risk for dementia although results have been inconsistent. There are no reported studies from the developing world including Africa. METHODS: In this longitudinal study of two community-dwelling cohorts of elderly Yoruba and African Americans, levels of homocysteine, vitamin B12 and folate were measured from blood samples taken in 2001. These levels were compared in two groups, participants who developed incident dementia in the follow-up until 2009 (59 Yoruba and 101 African Americans) and participants who were diagnosed as cognitively normal or in the good performance category at their last follow-up (760 Yoruba and 811 African Americans). Homocysteine levels were divided into quartiles for each site. RESULTS: After adjusting for age, education, possession of ApoE, smoking, and time of enrollment the higher quartiles of homocysteine were associated with a non-significant increase in dementia risk in the Yoruba (homocysteine quartile 4 vs. 1 OR: 2.19, 95% CI 0.95-5.07, p = 0.066). For the African Americans, there was a similar but non-significant relationship between higher homocysteine levels and dementia risk. There were no significant relationships between levels of vitamin B12 and folate and incident dementia in either site although folate levels were lower and vitamin B12 levers were higher in the Yoruba than in the African Americans. CONCLUSIONS: Increased homocysteine levels were associated with a similar but non-significant increase in dementia risk for both Yoruba and African Americans despite significant differences in folate levels between the two sites.

A novel high-sensitivity electrochemiluminescence (ECL) sandwich immunoassay for the specific quantitative measurement of plasma glucagon.

OBJECTIVES: To develop a novel, dual-monoclonal sandwich immunoassay with superior sensitivity that provides a rapid and convenient method for measuring glucagon. Glucagon is a 29-amino acid polypeptide hormone produced in the pancreas by the α-cells of the islets of Langerhans. Working in concert with insulin, glucagon is involved in regulating circulating glucose concentrations. DESIGN AND METHODS: The immunoassay utilizes Meso Scale Discovery (MSD) electrochemiluminescence (ECL) technology and two affinity-optimized monoclonal antibodies. A series of experiments was performed to determine the linear range of the assay and to evaluate sensitivity, accuracy, recovery, precision, and linearity. RESULTS: The sandwich assay was specific for glucagon and did not recognize the closely related peptide oxyntomodulin or other incretin peptides. The assay demonstrated excellent recovery, precision, and linearity, and a broad dynamic range of 0.14 pmol/L to 1950 pmol/L. In addition, assay results were highly correlated with those obtained using a previously described competitive RIA employing polyclonal antiserum. CONCLUSION: The use of affinity-optimized monoclonal antibodies in a sandwich immunoassay format provides a robust, sensitive, and convenient method for measuring concentrations of glucagon that is highly sensitive and specific. This immunoassay should help to improve our understanding of the role of glucagon in the regulation of glucose metabolism.